At present, the substances Zoladex® (INN: goserelin), Decapeptyl® (INN: triptorelin) and Leupron® (INN: leuprolide) are available for the therapy of hormone-dependent malignant diseases.
Zoladex® is injected under the skin in the form of an elongate cylinder 1 cm in length and 1 mm in diameter using a special applicator. Decapeptyl® is available in the form of a microcapsule emulsion which is likewise given subcutaneously. Leupron® is injected once every 4-month as a depot formulation. All forms ensure a continuous release of active compound to the surrounding tissue. The mechanism of action of all three substances is that of a superagonist.
The substance cetrorelix (INN) is an antagonist of LHRH. The mechanism of action differs completely from the known superagonists. Synthesis and some important pharmacological actions are described in U.S. Pat. No. 4,800,191 and U.S. Pat. No. 5,198,533. Other doses are therefore needed for therapy with cetrorelix.
For the complete suppression of the hormone concentration to castration level, a dose of 10 mg daily is necessary in volunteer tests amounting to at least 300 mg per month. This high daily dose cannot be accepted in sustained-release forms which are intended to act for a relatively long period of time, for example several months. The depot to be injected below the skin would be too voluminous and would no longer be tolerable.
U.S. Pat. No. 5,663,145 describes the use of initial high doses and maintenance doses of both LHRH antagonists in an animal study and volunteer trial. There, it is claimed that in DMBA-induced mamma-carcinoma in the rat with an initial high dose and a further dose which given by itself is not active, a therapeutic result could be achieved.
Further, in a volunteer trial over a period of three weeks, it was found that after the injection of an initial dose of 10 mg LHRH antagonist, which led to a complete suppression of LH, FSH and testosterone, a complete suppression of LH, FSH and testosterone could likewise be observed with maintenance doses of 1 mg every 12 hours, 2 mg every 24 hours and 1 mg every 24 hours.
U.S. Pat. No. 5,663,145 also describes corresponding pharmaceutical packs contain the active substance in an initial dose in the amount from 1-60 mg in a lyophilisate ampoule, and in a maintenance dose either in one or more lyophilisate ampoules containing a sustained-release form having a delivery rate of 0.1-10 mg/day for the entire therapy period or in lyophilisate ampoules with the amount of active substance which is not present in sustained-release form in an amount from 0.1-10 mg.
However, treatment according to U.S. Pat. No. 5,663,145 fails to prevent undesired hormone withdrawal symptoms, such as flare-ups, since complete hormone suppression (chemical castration) is effected and maintained for extended time over both periods of initial dose and maintenance dose treatment. Furthermore, insufficient initial dose are applied (1 to 60 mg, 10 mg as exemplified) whereby daily application of maintenance doses are necessitated. Such daily administration of maintenance doses of LHRH antagonist needed results in 30 injections per months, which is very inconvenient for the patients treated (patient compliance) and disadvantageous from an economical point of view (associated treatment costs).
U.S. Pat. No. 6,455,499 is directed to methods of treating disorders associated with LHRH activity. The treatment of prostate cancer, breast cancer and ovarian cancer is mentioned.
Example 6 describes a treatment regimen using compound #3827, where male rats are treated with among others initial doses of 300 μg/kg/day or 1000 μg/kg/day, which effect complete castration of the rats. Subsequently the animals were further treated with “low doses” of 5 μg/kg/day, 15 μg/kg/day or 50 μg/kg/day over 21 days. However, it is explicitly stated that all treated animals remained fully castrated over the entire treatment period.
Behre H M et al. describe high loading and low maintenance doses of GnRH antagonists whereby a suppression of initial high doses can be maintained by low dose injections (Behre H M et al., J. Clin. Endocrin. Metabol. 1997, 82(5): 1403-1408). The authors show that during the low maintenance dose period LH levels, FSH levels and testosterone levels were near the assay detection limit. Testosterone levels did at no time point exceed 2 nmol/L (page 1406, left column), which equals to 0.58 ng/mL testosterone (MWtestosterone=288.43 g/mol). Therefore, it is clear from the disclosure of Behre et al. that complete castration was achieved and maintained over both periods of initial dose and maintenance dose treatment.